On Target - Weekly Journal, Issue July 30, 2000

I	..	WHAT'S NEW Vacation Time
II		HISTORY OF MEDICINE Smallpox in Canada
III		WOMEN'S HEALTH Hyperparathyroidism and Osteoporosis Coronary Heart Disease
IV		AUTOIMMUNE DISEASE Epstein Barr Virus and Multiple Sclerosis Coffee and Rheumatoid Arthritis
V		PRIMARY PULMONARY HYPERTENSION (PPH) Gene Defect Identified
VI		CARDIOVASCULAR DISEASE Hemorrhagic and Ischemic Stroke Risk
VII		FDA Phases of Clinical Investigations
VIII		TARGET HEALTH INC.

Ms. Joyce Hays (CEO) and Dr. Jules T. Mitchel (President) will be taking their annual voyage to Santa Fe, NM on August 12 and return on August 26. We would like to wish you all well and thank you for helping to make this year the best to date for those of us at TARGET HEALTH. During our vacation the office is open and the wheels continue to churn. Please let us know how we can help you in your next project

Edward Jenner's first treatise in 1798 described how he used cowpox material to provide immunity to the related smallpox virus. He sent this treatise and some cowpox material to his classmate John Clinch in Trinity, Newfoundland, who gave the first smallpox vaccinations in North America. Dissemination of the new technique, despite violent criticism, was rapid throughout Europe and the United States. Within a few years of its discovery, vaccination was instrumental in controlling smallpox epidemics among aboriginal people at remote trading posts of the Hudson's Bay Company. Arm-to-arm transfer at 8-day intervals was common through most of the 19th century. Vaccination and quarantine eliminated endemic smallpox throughout Canada by 1946. The last case, in Toronto in 1962, came from Brazil.

TARGET HEALTH is committed to the study of Women's Health. Exciting new studies are being planned in the reproductive area with an NDA planned for submission in September of this year. The new program will involve extensive use of Target e*CRF for Internet-based data collection and project management. A manuscript is being prepared in the area of infertility,

According to an article published in Archives of Internal Medicine (Arch Intern Med 2000;160:2161-2166), postmenopausal women with primary hyperparathyroidism may have a new option for the treatment of osteoporosis. The data demonstrate that hormone replacement therapy (HRT) can be an effective alternative to parathyroidectomy in this population. Results from the study indicated that after 4 years, postmenopausal women with primary hyperparathyroidism who were using HRT had bone mineral densities (BMDs) ranging from 7% to 8% higher than those of similar women who were not treated. For the study, data were reported from a 2-year extension of a prior study of HRT in postmenopausal women with primary hyperparathyroidism, bringing the follow-up period to 4 years. The study population consisted of 23 patients, 11 of whom received HRT (conjugated equine estrogen, 0.625 mg/day, and medroxyprogesterone acetate, 5 mg/day), and 50 normocalcemic age-matched controls. At 4 years, BMD was significantly higher in patients taking HRT than in untreated patients, with a difference in total body BMD of 4.6%. The differences between the two groups in site-specific BMDs ranged from 6.8% in the legs to 8.2% in the femoral trochanter. Biochemical markers revealed lower rates of bone loss during the study in women using HRT than in untreated controls. Bone loss was also greater in untreated women with primary hyperparathyroidism than in normocalcemic controls. However, this difference was significant only for two sites: total body and legs. These findings extend the results of prior studies in this population, and suggest that the benefits of HRT in postmenopausal women with primary hyperparathyroidism are maintained for at least 4 years. The authors concluded that for women with primary hyperparathyroidism, HRT offers an important new therapeutic option for asymptomatic patients who do not have other indications for surgery.

According to an article published in the journal Heart (2000;84:189-192), myocardial ischemia in premenopausal women with coronary heart disease is more easily induced during the follicular phase of the menstrual cycle when estrogen concentrations are low. For the study, nine premenopausal women were evaluated who had a history of coronary heart disease. Each subject underwent exercise testing for myocardial ischemia as determined by time to 1-mm ST depression. The women's menstrual cycle stage was established by measuring hormone concentrations. It was found that the early follicular phase, when estradiol and progesterone concentrations were both low, was associated with the worst exercise performance in terms of time to onset of myocardial ischemia, at 290 seconds. It was also noted that the best exercise test performance, 418 seconds, occurred during midcycle when hormone concentrations were highest. Progesterone concentrations did not affect exercise performance. According to the authors, menstrual angina should be taken into account when interpreting symptoms and exercise tests in premenopausal women with angina.

The role of infectious agents and environmental factors has been suggested as etiologies of autoimmunity. The following two articles are timely.

According to an article published in the journal Neurology (2000;55:178-184), the Epstein-Barr virus (EBV) may play an indirect role in activating the underlying disease process of multiple sclerosis (MS). In the study, the prevalence of antibodies against herpes viruses, including EBV, was measured in the sera of 108 MS patients and 163 healthy control subjects. Antibodies against EBV were present in 100% of the MS patients and in 90.1% of the control subjects. Serologic signs of primary EBV infection were noted in 3.7% of healthy control subjects and in none of the MS patients. According to the authors, this indicates that EBV infection is a prerequisite for MS rather than a consequence of the disease. The authors also prospectively followed 19 MS patients monthly for one year. Increased immunoglobulin M and A responses to EBV early antigens and positive serum DNA were observed in 72.7% of patients with exacerbations during the study period. No EBV DNA could be amplified from the sera of clinically stable MS patients. The authors theorized that EBV reactivation may be indirectly involved in MS pathogenesis. They also noted that recent study findings have indicated that exacerbations are significantly reduced in MS patients treated with acyclovir. Taken together, these data suggest that a reduction of EBV replication in treated patients might likewise have influenced the outcome of the trial.

Rheumatoid arthritis (RA), an autoimmune disease, occurs when the immune system goes awry and attacks the joints, causing severe inflammation, pain and stiffness. RA afflicts about 1% of people, including more than 2 million Americans. Recent studies in the literature have raised suspicions about smoking and obesity. RA is not the type of arthritis common in the elderly because of the wear-and-tear of aging (Osteoarthritis).

According to an article published in Annals of the Rheumatic Diseases, a new study raises the possibility that people who drink a lot of coffee might be more likely to develop RA. Results of the study showed that people who drank more than three cups a day had twice the chance of getting RA as those who drank less. For the study, coffee drinking habits of 19,000 Finnish people was followed over 15 years. None had RA when the study began in the 1970s. By 1989, 0.5% of those who drank more than three cups of coffee developed RA while only about 0.2% of the people who drank three cups of coffee a day or less got the disease. The authors hypothesized that some unidentified ingredient in coffee may trigger the production of rheumatoid factor, an antibody that can be detected in the blood years before the onset of arthritis. Unfortunately, because the Finns are heavy coffee drinkers, there weren't enough non-coffee drinkers to make a comparison that might show how important a role coffee drinking might be.

TARGET HEALTH is proud to announce that Dr. Fred Reno is currently managing a toxicology program on behalf of one of our clients, in the area of pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a rare lung disease characterized by uncontrolled proliferation of cells in the blood vessels in the lungs. This build-up of cells leads to blockages in the blood vessels, forcing the heart to pump harder and increasing blood pressure in the pulmonary artery. The disease affects twice as many women as men, usually women of child-bearing age, although it can occur at any age, including infancy. The most common forms of treatment for advanced PPH are lung transplantation or continuous intravenous administration of prostacyclin to dilate or relax blood vessels. These treatments are expensive and difficult, and side effects are common. Before the availability of these treatments, survival following diagnosis of PPH was only 3 to 5 years. Even with treatment, life expectancy for PPH patients is very limited.

According to the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, one article has just been published in Nature Genetics and an other in the American Journal of Human Genetics describing a genetic mutation associated with PPH. Two research groups have independently reported that defects in the BMPR2 gene, which regulates growth and development of the lung, are associated with PPH. The defects in the gene lead to the abnormal proliferation of cells in the lung characteristic of PPH. Although both studies suggest that only one gene is involved in PPH, neither group has identified the defects in BMPR2 as the sole cause of PPH. In addition, since many people without a known family history of PPH get the disease, both groups suggested that other factors may interfere with control of tissue growth. The research is the culmination of nearly 20 years of work to identify possible immunologic and genetic factors in the cause and progression of PPH. The NHLBI created the first PPH Patient Registry in the world in 1981 to gain an understanding of the natural course of PPH. Some of the 194 patients in the Registry participated in the studies. The next step will be to determine whether people with sporadic PPH, where there does not appear to be a family history, carry the same defect.

TARGET HEALTH Medical Writing Group led by Anita Islam, Ph.D. and Daisy Sun, M.S., has completed writing a key study report and manuscript for a Fortune 100 company in the area of systolic hypertension. We will let you know when it is published.

According to an article published in The Journal of the American Medical Association (JAMA 2000;284:465-471), the incidence of both hemorrhagic and ischemic stroke can be reduced by lowering blood pressure in elderly patients with hypertension. In a multicenter study, data were collected on 4,736 hypertensive men and women, 60 years of age and older, who were participants in the Systolic Hypertension in the Elderly Program (SHEP). At baseline, systolic blood pressure in the subjects ranged from 160 to 200 mm Hg. Patients were randomized to receive either placebo or active treatment, which consisted of chlorthalidone plus atenolol or reserpine, if needed. At the start of the 5-year trial there were 2,365 patients in the treatment group and 2,371 in the placebo group. It was found that the active treatment had the same effect on the incidence of both hemorrhagic and ischemic strokes, although not on arthrosclerotic strokes. In addition, in the treatment group, there were fewer hemorrhagic strokes during the first year but as many ischemic strokes as in the placebo group. Not until the second year was there a reduction in ischemic strokes in the treatment group compared to the placebo group. The authors stated that while the differences were not statistically significant, the differences were considerable. Compared with the placebo group, many more of the patients on active treatment reached the goal of systolic blood pressure less than 160 mm Hg. If the blood pressure was reduced below 160 mm Hg, whether through active treatment or placebo, the chance of developing a stroke was decreased by about a third. If the blood pressure was reduced below 150 mm Hg, the risk was decreased a bit more. Below 140 was not statistically significant, probably because there were fewer patients in that group.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA. A pre-IND meeting is scheduled for the first week in October. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available. For additional information, please contact Dr. Jules T. Mitchel at TARGET HEALTH.

Many of our readers are expert in the clinical development process through FDA. However, since we have a wide variety of readers, some may appreciate the following outline of the drug development process:

The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. The three phases of an investigation are as follows:

Phase 1 includes the initial introduction of an investigational new drug into humans. These studies are usually, but not always, conducted in healthy volunteer subjects. In cancer and AIDS, only patients are tested first. Phase 1 studies are designed to determine the metabolic and pharmacological actions of the drug, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. Phase 1 studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. The total number of subjects included in Phase 1 studies is generally in the range of 20 to 80.

Phase 2 includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase 2 studies usually involve several hundred people.

Phase 3 studies are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase 3 studies usually include several hundred to several thousand people.

TARGET HEALTH INC. is a full service CRO with full-time staff dedicated to all aspects of Regulatory Affairs, including IND, IDE, NDA, and PMA submissions, Clinical Research Management, Medical Writing, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEATH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic planning from discovery to market launch. Let us help you on your next project.

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Last modified: August 08, 2000